Problem Description

4-hydroxyphenylpyruvate dioxygenase (HPPD) is an enzyme involved in the breakdown of excess tyrosine, an amino acid, in the body of mammals. It is present mainly in the liver. One inhibitor of HPPD is used successfully as a pharmaceutical, where it acts by blocking the tyrosine breakdown pathway. However, the inhibition of HPPD can result in toxicities in some species, especially rats. In plants the same enzyme has a completely different role, being essential for the synthesis of components needed for photosynthesis. The inhibition of HPPD is the mode of action of a number of commercialised herbicides, as this inhibition causes bleaching and ultimately death of the plant.

A variety of in silico, in vitro and in vivo information is now available. The challenge is to suggest ways of making better use of the existing database to assess the potency and safety of new HPPD inhibitors. In particular, to explore the extent to which in silico and in vitro information can be used to predict in vivo outcomes in mammals.

Can the Study Group participants suggest ways of making better use of existing databases on relevant pathways to assess the potency of new HPPD inhibitors. In particlular:

Can existing information be used to better predict in vivo outcomes for novel HPPD inhibitors?

What insights are to be had on the relationship between in vitro and in vivo data?

Can we better understand the relationship between mouse, rat and human responses in vivo?

Can we use models to better address these questions?

Can we use the data to better separate toxicity to plants and mammals

What new data would increase the ability to make in vivo predictions based on in vitro data.